This invention relates to devices and methods for the treatment of ischemic tissue. In particular, the devices and methods initiate fibrin formation at sites in the ischemic region to promote angiogenesis and vessel recruitment, which revascularizes the ischemic tissue.
Tissue becomes ischemic when it is deprived of adequate blood flow. lschemia causes pain in the area of the affected tissue and, in the case of muscle tissue, can interrupt muscular function. Left untreated, ischemic tissue can become infarcted and permanently non-functioning. Ischemia can be caused by a blockage in the vascular system that prohibits oxygenated blood from reaching the affected tissue area. However, ischemic tissue can be revived to function normally despite the deprivation of oxygenated blood because ischemic tissue can remain in a hibernating state, preserving its viability for some time. Restoring blood flow to the ischemic region serves to revive the ischemic tissue. Although ischemia can occur in various regions of the body, often myocardial tissue of the heart is affected by ischemia. Frequently, the myocardium is deprived of oxygenated blood flow due to coronary artery disease and occlusion of the coronary artery, which normally provides blood to the myocardium. The ischemic tissue causes pain to the individual affected.
Treatment of myocardial ischemia has been addressed by several techniques designed to restore blood supply to the affected region. A conventional approach to treatment of ischemia has been to administer anticoagulants with the objective of increasing blood flow by dissolving thrombus or preventing formation of thrombus in the ischemic region.
Another conventional method of increasing blood flow to ischemic tissue of the myocardium is coronary artery bypass grafting (CABG). One type of CABG involves grafting a venous segment between the aorta and the coronary artery to bypass the occluded portion of the artery. Once blood flow is redirected to the portion of the coronary artery beyond the occlusion, the supply of oxygenated blood is restored to the area of ischemic tissue.
Early researchers, more than thirty years ago, reported promising results for revascularizing the myocardium by piercing the muscle to create multiple channels for blood flow. Sen, P. K. et al., xe2x80x9cTransmyocardial Acupuncturexe2x80x94A New Approach to Myocardial Revascularizationxe2x80x9d, Journal of Thoracic and Cardiovascular Surgery, Vol. 50, No. 2, August 1965, pp. 181-189. Although researchers have reported varying degrees of success with various methods of piercing the myocardium to restore blood flow to the muscle (which has become known generally as transmyocardial revascularization or TMR), many have faced common problems such as closure of the created channels. Various techniques of perforating the muscle tissue to avoid closure have been reported by researchers. These techniques include piercing with a solid sharp tip wire, or coring. with a hypodermic tube. Reportedly, many of these methods produced trauma and tearing of the tissue that ultimately led to closure of the channel.
An alternative method of creating channels that potentially avoids the problem of closure involves the use of laser technology. Researchers have reported success in maintaining patent channels in the myocardium by forming the channels with the heat energy of a laser. Mirhoseini, M. et al., xe2x80x9cRevascularization of the Heart by Laserxe2x80x9d, Journal of Microsurgery, Vol. 2, No. 4, June 1981, pp. 253-260. The laser was said to form channels in the tissue that were clean and made without tearing and trauma, suggesting that scarring does not occur and the channels are less likely to experience the closure that results from healing. U.S. Pat. No. 5,769,843 (Abela et al.) discloses creating laser-made TMR channels utilizing a catheter based system. Abela also discloses a magnetic navigation system to guide the catheter to the desired position within the heart. Aita U.S. Pat. Nos. 5,380,316 and 5,389,096 disclose another approach to a catheter based system for TMR.
Although there has been some published recognition of the desirability of performing TMR in a non-laser catheterization procedure, there does not appear to be evidence that such procedures have been put into practice. U.S. Pat. No. 5,429,144 (Wilk) discloses inserting an expandable implant within a preformed channel created within the myocardium for the purposes of creating blood flow into the tissue from the left ventricle.
Performing TMR by placing stents in the myocardium also is disclosed in U.S. Pat. No. 5,810,836 (Hussein et al.). The Hussein patent discloses several stent embodiments that are delivered through the epicardium of the heart, into the myocardium and positioned to be open to the left ventricle. The stents are intended to maintain an open channel in the myocardium through which blood enters from the ventricle and perfuses into the myocardium.
Angiogenesis, the growth of new blood vessels in tissue, has been the subject of increased study in recent years. Such blood vessel growth to provide new supplies of oxygenated blood to a region of tissue has the potential to remedy a variety of tissue and muscular ailments, particularly ischemia. Primarily, study has focused on perfecting angiogenic factors such as human growth factors produced from genetic engineering techniques. It has been reported that injection of such a growth factor into myocardial tissue initiates angiogenesis at that site, which is exhibited by a new dense capillary network within the tissue. Schumacher et al., xe2x80x9cInduction of Neo-Angiogenesis in Ischemic Myocardium by Human Growth Factorsxe2x80x9d, Circulation, 1998; 97:645-650.
Encouraging the initiation of naturally occurring angiogenic mechanisms within tissue such as the release of growth factors during coagulation and fibrin formation would be a desirable method of treating ischemic tissue. It has been recognized that coagulation proteases and regulatory acting during thrombus formation may initiate vascular proliferative responses. Robert S. Schlant (et al.), The Heart (1994).
A general object of the present invention is to initiate the body""s injury response mechanisms, of which fibrin formation is a part, to treat ischemia. Treatment with the devices and methods of the present invention is considered to be contrary to conventional wisdom in view of the currently known methods of revascularization discussed above. Furthermore, the inventive devices and methods may provide more promising results because they utilize the body""s own healing response as a mechanism of treatment.
The present invention provides devices and methods for promoting revascularization in tissue by initiating fibrin growth in that tissue. The devices and methods are intended to be useful in any tissue of the human body. However, the invention is most useful for treatment of ischemic tissue which has remained viable despite previous deprivation of adequate blood flow and would benefit from revascularization that occurs from the process of angiogenesis and vessel recruitment. Furthermore, because ischemic tissue has suffered injury, it may experience an injury response and be better conditioned to respond to the mechanisms that promote fibrin growth.
The invention utilizes the body""s own healing process, the process of fibrin formation known as the coagulation cascade effect, to induce angiogenesis and recruitment of existing vessels to the ischemic region. The coagulation cascade is known to be initiated by injury or aggravation of the tissue. Aggravation may be mechanically or chemically induced. As a result of the tissue injury, collagen and connective tissue are exposed to blood. The injury activates platelets and, by either an intrinsic (factor XII is activated) or extrinsic (factor VII is activated) pathway, thrombin is produced. Thrombin is a catalyst that changes available fibrinogen into fibrin (a fibrous network formation). Fibrin helps to promote angiogenesis because its fibrous network provides a host structure for endothelial cells, which will form the new blood vessels to the ischemic area. Additionally, thrombin that has been produced and remains in the fibrin network serves to direct the endothelial cells to migrate and proliferate so that new vessels are formed to the fibrin area. The devices and methods of the present invention promote and sustain a localized area of fibrin growth, a fibrin plug, which releases growth factors helpful in recruiting existing adjacent vessels to the area of ischemic tissue, thereby supplying it with blood flow.
Both angiogenesis and recruitment of existing vessels are important mechanisms of revascularization that are initiated by practice of the present invention. Growth of new vessels to the fibrin plug area helps to expand and increase the density of the vascular bed. However, the new vessels may dissipate after the fibrin plug eventually is dissolved. Sustaining the fibrin growth permits existing vessels in adjacent tissue locations to be recruited, redirected, to the fibrin area to provide a sustained supply of oxygenated blood flow to the developing vascular bed. Growth factors released during the coagulation cascade reach adjacent vessels and redirect them to the site of fibrin formation. Capillaries and arterioles can be recruited to the ischemic region and serve to revascularize the tissue and supply the new vessels that have formed with blood.
The approach of promoting coagulation and fibrin growth to revascularize tissue is a departure from of conventional treatments that focus on increasing blood flow through existing pathways such as by thinning the blood and preventing thrombosis. Conventional treatments for ischemia have concentrated on preventing the clotting of blood so that blood may flow more freely to reach areas of reduced flow. Generally, thrombosis is considered to hamper blood flow and, therefore, to complicate conditions marked by reduced blood flow, such as ischemia. Conventional treatments to increase blood flow to a region include administration of anticoagulants, such as heparin, or fibrinolytic agents, which prevent the formation of fibrin. However, the present invention has resulted from the recognition that those very factors considered undesirable, such as fibrin and thrombus formation, can be used to treat ischemia because they initiate the growth of new blood vessels and the recruitment of existing vessels to the region. Angiogenesis can be initiated from fibrin formation, which results from the process of blood coagulation. Additionally, the presence of fibrin causes existing vessels in adjacent tissue to be redirected to the fibrin site.
The devices of the present invention are configured to promote fibrin and thrombus formation, which is contrary to conventional vascular implant device design. Commonly, devices that are implanted in an environment exposed to blood, such as in vascular applications, are configured, by their material, profile or by application of a coating, to be anti-thrombogenic. Conventional medical device design dictates that implant devices exposed to blood must be configured to resist thrombus formation so that blood flow around the device will not become restricted. The devices disclosed herein are configured to maximize thrombus formation in contrast to the prior art, which attempts to minimize thrombosis.
The present invention is intended to be useful in any tissue of the body that has become ischemic because of reduced blood flow to the region. For example, the legs commonly suffer from reduced blood flow that leads to ischemia of the muscle tissue in those regions. Also, the present invention is believed to provide particular benefit in the treatment of ischemic myocardial tissue of the heart. Restricted blood flow to the heart tissue is commonly caused by blocked coronary arteries. The ischemia that results from the reduced blood flow causes severe chest pain. The present invention provides treatment for ischemic myocardial tissue by promoting angiogenesis and vessel recruitment in the region to revascularize the ischemic tissue. It is emphasized, however, that the devices and methods herein disclosed are applicable to any area of body tissue in which it is desirable to promote revascularization. Furthermore, multiple devices can be implanted, or procedures performed, to initiate multiple sites of fibrin growth and vascularization activity in a region of tissue.
One embodiment of the invention comprises an device that is implanted into tissue and is configured to promote fibrin growth within the tissue. The implant device may be formed in a variety of configurations, but should comprise a structure or frame, flexible or rigid, having a region where fibrin growth may be fostered and held in association with the implant device. The fibrin retention region may be on the interior or exterior of the device. However, the device should be configured to permit communication between the associated fibrin and the surrounding tissue into which the device has been implanted. Blood, carrying agents of fibrin formation, must be permitted to flow to and from the fibrin network so that blood vessels will grow to the area of the fibrin plug. Additionally, the new and recruited blood vessels should have access to the fibrin growth so that permanent blood pathways to the ischemic area can be formed.
The formed fibrin should be securely associated with the implant device. If the fibrin is retained in an interior chamber of a device, openings between the interior and exterior of the device should be sized to be smaller than the size of the formed thrombus to capture the fibrin. If the device is configured to maintain fibrin on its exterior, the fibrin must be formed to the surface, adhered the device or retained in a matrix that can be adhered to the device, such as a thrombophilic coating.
The device and associated fibrin should be securely anchored in the tissue to prevent migration from the tissue and into the blood stream. It would be undesirable to have fibrin to enter the blood stream, becoming an emboli that may become lodged in an artery to a critical organ such as the brain or heart, possibly blocking blood flow to that organ. An implant device may tend to migrate when placed in active muscle tissue such as the myocardium. Cyclic contraction and relaxation of surrounding tissue can serve to push the implant out of its original implant location. Anchoring may, but need not, involve a dedicated component on the device such as a projection that claws into surrounding tissue. Anchoring also may be accomplished by configuring the device to have an overall shape that resists movement through the tissue. Furthermore, the method of delivery and placement of the device in the tissue may insure sufficient anchoring to prevent migration, without a specific anchor structure being associated with the device.
The devices may be configured to cause injury and irritation to surrounding tissue. Injury triggers a healing response in tissue leading to fibrin growth. Therefore, a device configured to cause injury while implanted helps to initiate and sustain the injury response and resulting coagulation, maximizing and maintaining the fibrin growth generated by the device. The device may be configured to irritate the tissue, either biologically or mechanically. A number of agents may be applied to the device to cause an adverse biological reaction in surrounding tissue or the device maybe formed of material that irritates tissue, such as a polymer. Mechanical irritation may be accomplished by configuring the device to have surfaces that irritate tissue, such as protrusions. The surfaces of the device serve to slightly injure the tissue during frictional contact between device and surrounding tissue. The frictional contact with the tissue occurs not only during implantation, but also, in the case of muscle tissue, constantly thereafter as the muscle relaxes and contracts.
The devices may be solid structures or may be hollow and define an interior chamber. Hollow structures may include, for example, mesh tubes, coils or capsules. Regardless of the exact configuration of a hollow device, if the interior chamber is intended to foster fibrin growth, it must be in communication with tissue that surrounds the implanted device. Agents of fibrin growth, such as thrombin, growth factors and endothelial cells should be free to flow between surrounding tissue and the fibrin growth. For example, pores or openings through the surface of the device should be present so that the substances that promote fibrin growth, and eventually new and recruited vessels, can flow between the interior chamber and exterior of the device.
The devices may be permanent or biodegradable. Also, the devices may have associated with them substances that promote fibrin formation or endothelial cell formation, such as growth factors. In the case of biodegradable implants, fibrin forming agents may be embedded in the biodegradable material so as to be released during the degradation of the material. The substance is released gradually into the surrounding tissue as the material degrades to promote fibrin growth. In the case of permanent implants, a growth factor or fibrin producing substance may be applied by coating the surfaces of the device with the substance or with a composition that serves to host the substance. The substance is released from the coating of the device over time as the coating dissolves or as blood gradually carries it away from the coating matrix.
Another method of enhancing the angiogenic effect of the implant is by associating with the implant a thrombus (advanced fibrin growth) formed from blood previously removed from the body. The thrombus may be formed within the interior chamber of a hollow device ex vivo or preformed ex vivo first, then placed into the interior prior to or after implantation. In the case of a solid device, the fibrin may be permitted to form around the exterior of the device ex vivo before it is implanted in tissue. The formed thrombus may hasten revascularization in the subject tissue by providing a ready made completed fibrin network into which growth factors and endothelial cells may be attracted. Also, the formed thrombus could be preloaded with growth factors or other agents, thereby serving as a natural, biodegradable host network for the angiogenic agents.
A thrombophilic substance also may be associated with the device prior to implantation to increase the angiogenic effect of the device. The thrombophilic substance collects and retains blood present in the tissue into which the device has been implanted. The retained blood will tend to coagulate in vivo, beginning the coagulation cascade, which leads to the formation of a fibrin plug. The coagulation promoted by the thrombophilic substance tends to maximize the fibrin growth resulting from placement of the device, which enhances the revascularative effect of the implant.
An alternative method of the invention involves placing a thrombus or fibrin producing substance, or a thrombophilic substance, directly into the tissue to be treated without an associated device. As explained above, the presence of such substances in tissue, with blood present, enhances fibrin production and its associated revasculative effect. Therefore, as an alternative to implanting a device, fibrin producing substances alone may be administered to induce fibrin growth.
It is an object of the present invention to provide devices and methods to stimulate fibrin growth and its associated revascularative effect.
It is another object of the invention to provide a reliable treatment for ischemia whereby ischemic tissue is revascularized by new and recruited vessels.
It is another object of the invention to provide a method of treating ischemia that utilizes the body""s own physiological responses by fostering fibrin growth in the ischemic tissue.
It is another object of the invention to provide a method of promoting angiogenesis in tissue.
It is another object of the invention to provide treatment for ischemia that is safe and reliable for the patient.
It is another object of the invention to provide methods and devices for revascularizing myocardial tissue by creating a fibrin plug in an ischemic region.
It is another object of the invention to provide an implant device configured to promote thrombus formation.